Poorly controlled diabetics are more subject to infection than are non-diabetics. The problem may be due in part to an impairment of neutrophil function since a real, but variable, degree of neutrophil dysfunction has been shown to occur in such individuals. Consequently, we propose to study this impairment by cell biological techniques and analyze the functions of diabetic polymorphonuclear leukocytes (PMN) in host defense. Responses to a variety of immune stimuli will be studied in both diabetic and control human leukocytes. Among the parameters to be examined are adherence, chemokinesis and chemotaxis, O2- generation, phagocytosis, and the kinetics of enzyme release. Ultrastructural studies will include the analysis of electronmicroscopic stereology of the cellular rearrangement undergone by diabetic and control PMN exposed to immune stimuli, particularly with reference to lysosomal enzyme discharge and the functional state of microtubules and microfilaments. Ultrastructural carbohydrate cytochemistry will be used to study the intracellular distribution of glycoproteins and glycogen. The effects on these parameters of hormones, e.g., insulin, glucagon, glucocorticoids and catecholamines, will be examined as will those of known modifiers of leukocyte function, such as cyclic nucleotides, ionophores, ion transport blockers, and agents that influence the redox state of the cell. Defined agents will be studied to determine which, if any, are capable of influencing or mimicking the effects of poorly controlled diabetes. Parallel in vivo studies will be carried out in experimental diabetic animals, both insulin deficient (alloxan-treated) and insulin resistant (db/db mice). These will include studies of adherence, chemotaxis, and enzyme release. Of special concern will be an in vivo investigation of the effects of basement membrane thickening on PMN diapedesis.